PROJECT SUMMARY Various neuromuscular diseases result in impaired cough (dystussia). Disorders of these airway protective behaviors increase pulmonary infection due to aspiration, the leading cause of death in neuromuscular disease. Mortality rates of aspiration pneumonia - present in over half of long-term care residents - can approach 40%. Defense of the airway is achieved through coordination of multiple protective behaviors by brain circuits that remain incompletely understood. A contemporary data-driven computational model incorporating the brainstem network for breathing can rapidly reconfigure to produce the three phases a cough motor pattern: inspiration, compression, and expulsion. However, critical elements of airway protection cannot be explained. Based on motivating preliminary data and network simulations, we propose that a circuit in the nucleus of the solitary tract (NTS) and dorsal medulla regulates phase timing and respiratory muscle drive during paroxysmal coughs and exerts a command function over the brainstem respiratory control system to coordinate coughing and breathing. The project has 3 Specific Aims: (1) Determine dynamic behavior- dependent organization of NTS circuits during the expression of airway protective behaviors. (2) Determine functional connectivity between NTS and VRC neurons during expression of coughing. (3) Reconstruct our respiratory system model to incorporate regulation of both airway protective reflexes and breathing. Our unique approach, building upon experimental interrogation of the NTS region, incorporates multi-array recording technologies in an animal model system that generates defensive behaviors in response to physiologically relevant airway perturbations. We anticipate that the project will lead to: a) a new, predictive model of airway protection will be produced, b) we will understand functional relationships between conditionally active cells and t-E NTS neurons in producing cough, and c) we will identify critical NTS to parafacial/VRC functional relationships that regulate cough and breathing. This new knowledge will provide a critical step in understanding the neurogenesis of cough and how this behavior is controlled to protect the airway.